Abstract Severe neuronal loss characterizes Alzheimer's disease (AD). However, the mechanisms by which neurons die remain elusive. Additionally, it is also unclear why some neurons within the same brain region are more resistant to neurodegeneration than others. In this application, we will attempt to address these two critical issues. We focus on necroptosis, a programmed form of necrosis, triggered by receptor-interactive protein kinases (RIPK) 1 and 3 and executed by the mixed lineage kinase domain-like (MLKL) protein. Upon activation by multiple inflammatory stressors, RIPK1 can trigger cell survival or cell death pathways, with the former being a default response to inflammatory stimuli. This default survival pathway is regulated, among others, by the Lys63- deubiquitylating enzyme cylindromatosis (CYLD) and MAPKAP kinase-2 (MK2), which ubiquitinate and phosphorylate RIPK1, respectively. We provide compelling evidence showing that necroptosis is activated in postmortem human AD brains and it correlates with Braak stage, brain weight, and tau pathology. We further show that blocking necroptosis in a mouse model of AD reduces neuronal loss. These novel and exciting data, together with the experiments proposed here, may answer two key but unresolved questions: 1. Which mechanisms do govern cell loss in AD? 2. What does make some neurons more susceptible to neurodegeneration than others? Our overarching hypothesis is that necroptosis contributes to neurodegeneration and selective neuronal vulnerability in AD. Specific Aim 1 will identify the mechanisms linking RIPK1 activation to necroptosis induction in AD. Specific Aim 2 will identify the mechanistic link between RIPK1 and tau. Specific Aim 3 will determine the role of RIPK1 in the gene expression dysregulation observed in AD. Impact: Neuronal loss is a cardinal feature of AD and invariably affects multiple brain regions. Despite this indisputable evidence, the mechanism by which neurons die is still unknown. We propose that necroptosis is a key mechanism by which neurons die in AD and propose experiments to dissect the role of this pathway in AD fully. Our results will open new opportunities for research and interventions for this insidious disorder. From a basic biology perspective, these studies will uncover new and critical knowledge into the pathogenesis of this disease. From a therapeutic perspective, these studies will determine to what extent targeting necroptosis might be a valid approach to mitigate neuronal loss in AD.